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Biomedical subjects

M MacDonald

Publications and source records attributed to M MacDonald.

At least 73 records · Page 4Linked to original sources
PubMed1989

The medicalization of suicide in England: laymen, physicians, and cultural change, 1500-1870.

Defining a behavior as a medical problem can change both its moral and legal consequences. Responses to suicide were secularized in the late seventeenth and eighteenth centuries as coroners' juries increasingly adopted the medical explanation for self-destruction and excused suicides as innocent lunatics who were not criminally responsible for their act. It was medical laymen, however, not physicians, who were the principal champions of the medical explanation as they sought to alleviate the effects of the suicide laws on survivors. The change in societal attitudes and responses to suicide illustrates both the negotiated quality of disease definition and the way in which formal medical thinking constituted only one factor in a diverse political, religious, and cultural context.

Depression↗
PubMed1988

Western blot analysis of antigens on melanoma cells recognized by cytotoxic T cells.

Antigens recognized by cloned cytotoxic T lymphocytes (CTLs) from patients with melanoma were examined by methods based on the ability of antigens immobilized on nitrocellulose paper to stimulate proliferation of the CTLs. The proliferative response depended on the presence of histocompatible antigen-presenting cells (APCs) in the cultures in the form of either autologous lymphoid cell lines (Epstein-Barr virus-transformed B cells) or histocompatible peripheral blood lymphocytes and was maximal at 3 days. Presentation appeared to be via class II major histocompatibility complex antigens, in that monoclonal antibodies (MAbs) against the class II antigens, but not the class I antigens, on the APCs inhibited the proliferative responses. The response the CTLs appeared to be mediated by interaction with the alpha beta CD3 T-cell receptor complex, in that pretreatment of the CTL clones with MAbs against CD3 inhibited the response of these clones to the antigen extracts irrespective of the phenotypes of the clones. Extracts from several nonmelanoma cells did not stimulate CTL clones specific for melanoma. At least two different specificities were detected in extracts from autologous and allogeneic tumor cells. The specificity of proliferative responses by CD3+ CD4+ and CD3+ CD8+ CTLs appeared to be similar to their cytotoxic activity, but CTLs with the CD3+ CD16+ CD8+- phenotype had wider cytotoxic activity against target cells not stimulating proliferative responses. The antigen(s) responsible for the stimulation were shown in all instances to have a molecular mass of 48 kilodaltons. Preliminary analysis suggested that the antigen(s) have both protein and glycolipid (ganglioside) components.

Antigen-Presenting Cells↗
PubMed1988

Suppression of natural killer cell activity in humans by radiation from solarium lamps depleted of UVB.

Previous studies have shown that ultraviolet radiation (UVR) from solarium lamps suppressed natural killer (NK) cell activity in the blood and that sunscreen lotions offered no protection against this effect. In the present study we tried to determine whether the effects on NK cell activity were caused by the UVB or the UVA components of radiation from solarium lamps by filtering out UVB with Mylar sheeting. Groups of 10 normal subjects were either left untreated or exposed for 30 min on 12 consecutive days to radiation that was filtered or not filtered through a 0.1 mm thick Mylar sheeting. NK cell activity was depressed in the group exposed to solarium radiation and this was not prevented by filtration through Mylar. The latter procedure, however, appeared to prevent changes in blood lymphocyte subsets that are induced by solarium radiation as well as the reduction in Langerhans cell numbers in skin biopsies taken after exposure to solarium radiation. Suppression of NK cell activity was evident up to 14 days after cessation of UVR exposure. This would be consistent with the replacement of NK cells from bone marrow that had been damaged as a result of direct effects of UVA on NK cells in the microcirculation of the skin or else indicate functional suppression of NK cells by suppressor cells induced by UVR as postulated for UVR-induced suppression of delayed hypersensitivity responses in murine models. These studies suggest that UVA may be important in the induction of certain effects on the immune system in human subjects. Further studies are required to assess the implications of these findings with respect to induction of neoplasia and the design of sunscreens effective against UVA.

Adult↗
PubMed1987

Enhancement of cytotoxic and proliferative responses of lymphocytes from melanoma patients by incubation with monoclonal antibodies against ganglioside GD3.

Previous studies have shown that monoclonal antibodies (M.Ab) to the ganglioside GD3 may induce partial remissions in tumour growth in patients with melanoma. In vitro studies demonstrated that M.Abs to GD3 may also enhance lymphocyte responses to phytohemagglutinin and interleukin 2 (IL2). The present study extended these findings by showing that the IL2-dependent proliferative and cytotoxic response of T cell clones derived from a melanoma patient and a patient with the Vogt-Koyanagi-Harada syndrome were enhanced by pre-incubation of T cells with M.Ab to GD3. The degree of enhancement increased with the duration of pre-incubation from 2 to 24 h and applied to both T4+ and T8+ clones. The potentiation of these responses was not specific for M.Abs to GD3 but was also seen with M.Abs to GD2 and the T10 structure on T cells but not with M.Abs to the transferrin receptor or an isotype control M.Ab. Incubation of lymphocytes from a melanoma patient with M.Ab to GD3 during culture with autologous melanoma cells enhanced the proliferative response to the tumour. The expression of IL2 receptors (Tac epitope) on the T cells showed variable enhancement after incubation with M.Ab to GD3 but the significance of these findings in relation to the mechanism of the enhanced responses is not known. These results suggest that certain M.Abs may stimulate cell-mediated immune responses against tumour cells and that this may provide an additional mode of action of M.Abs against tumours in vivo.

Antibodies, Monoclonal↗
PubMed1987

Analysis of the effect of a sunscreen agent on the suppression of natural killer cell activity induced in human subjects by radiation from solarium lamps.

Previous studies in rodents have shown that ultraviolet radiation (UVR) may have direct effects on the immune system in the skin and at higher doses may induce systemic suppression of immune responses. We have previously shown that UVR from sun or solarium beds may induce systemic effects in human subjects. The purpose of the present study was to examine whether these systemic effects in human subjects could be prevented by use of commercially available sunscreen agents. Groups of 12 normal subjects were exposed to radiation from solarium lamps after application of a sunscreen agent or the base used in its preparation. Twelve half-hourly exposures induced a depression of natural killer (NK) cell activity against a melanoma and the K562 target cell which was not prevented by use of the sunscreen agent. Changes in functional activity were accompanied by a reduction in NK cell numbers assessed by Leu-11 monoclonal antibodies against the labile Fc receptor. Application of the sunscreen agent also did not protect against effects of solarium exposure on recall antigen skin tests and immunoglobulin production in vitro in pokeweed mitogen-stimulated cultures of B and T cells. These results suggest that further evaluation of the wave-length spectrum of UVR and the effectiveness of sunscreen agents in prevention of UVR-induced effects on the immune system is needed.

B-Lymphocytes↗
PubMed1987

The early enhancer-promoter of BKV and host range for transformation.

The early genes of the human papovavirus BKV and simian virus 40 (SV40) show a different host range for transformation. The early region of SV40 efficiently transforms human fibroblast cells, whereas the early region of BKV does not. Interchanging noncoding enhancer-promoter sequences around the origin of replication between BKV and SV40 showed that the early enhancer-promoter sequences of BKV and SV40 could substitute for each other, as far as the induction of expression of tumor antigens and morphological transformation is concerned; the efficiency of transformation was influenced by the enhancer-promoter sequences, and the difference in host range for transformation between BKV and SV40 was determined by the early gene products rather than by the enhancer-promoter sequences.

Animals↗
PubMed1986

Immunological effects of recombinant interferon alfa-2a in patients with disseminated melanoma.

Twenty patients with disseminated melanoma were treated with interferon alfa-2a, given by intramuscular (IM) injection three times a week in escalating doses from 15 to 50 X 10(6) U/m2. Of 18 patients considered evaluable, two had complete remission and in two others the disease was stabilized. Laboratory tests 6 hours after injection of interferon alfa-2a indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity. Sequential changes (measured before injection of interferon alfa-2a on days 3, 10, and 31) consisted of neutropenia, thrombocytopenia, and a slight increase in OKT4 positive T cells compared with OKT8 positive T cells. NK activity against the K562 target cells was increased in most patients during the first week of treatment, returning to near or below pretreatment levels thereafter. This response contrasted with a delayed increase against melanoma target cells in 10 patients. The latter correlated with an increase in mitogen-stimulated interleukin-2 (IL2) production, and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. Changes in cortisol levels may explain some effects on the immune system, such as depression of IL2 and immunoglobulin production in vitro, and the differences noted in clinical responses during the present study compared with those observed with interferon alfa-2b given by intravenous (IV) injection in 5-day cycles. These results suggest that interferon alfa-2a has antitumor activity in certain melanoma patients, in particular those with metastases to pulmonary or subcutaneous sites. Assays of IL2 production and LAK activity may assist in the selection of patients who respond to interferon alfa-2a and help to optimize treatment regimens.

Adult↗
PubMed1986

Phase II study of vaccinia melanoma cell lysates (VMCL) as adjuvant to surgical treatment of stage II melanoma. II. Effects on cell mediated cytotoxicity and leucocyte dependent antibody activity: immunological effects of VMCL in melanoma patients.

Patients with stage II melanoma were vaccinated with vaccinia virus-induced melanoma cell lysates (VMCL). The vaccine contained viable vaccinia virus, membranous fragments and no intact nuclei. A number of antigens defined by monoclonal antibodies were detected in the vaccine including the ganglioside GD3 and DR antigens. Administration of the vaccine was associated with depression of natural killer cell activity against melanoma and K562 target cells in the first 3-6 months of treatment. Leucocyte dependent antibody (LDA) activity against melanoma cells was induced or increased in titre in approximately half of the patients studied. Continued vaccination was associated in a number of patients with a decrease in LDA titres. Studies on a small sample of patients revealed that this was associated with the development of serum factors which inhibited LDA activity. LDA activity appeared directed to non-MHC antigens on melanoma cells which were of at least two specificities. One specificity which was shared with antigens on a number of non-melanoma carcinoma cells was removed by absorption on fetal brain and may be similar to oncofetal antigens described by other workers. Reactivity against melanocytes was induced in some patients and may underline the development of vitiligo in several patients. These results suggest that vaccines prepared from VMCL may be a favourable method for increasing immune responses against melanoma.

Antibodies, Neoplasm↗
PubMed1986

Clonal analysis of cytotoxic T lymphocytes (CTL) against autologous melanoma. Classification based on phenotype, specificity and inhibition by monoclonal antibodies to T cell structures.

This study investigates the nature and specificity of cytotoxic T lymphocytes (CTL) in patients with melanoma which are able to kill autologous melanoma cells. Interleukin 2 (IL2)-dependent T cell clones from two melanoma patients and a normal subject were generated in mixed lymphocyte cultures (MLC) or mixed lymphocyte tumor cell cultures (MLTC) and propagated for prolonged periods in tissue culture. Analysis of their phenotype by a wide range of monoclonal antibodies (M.Abs) revealed two main phenotypes which depended on whether they expressed Fc receptors detected by Leu 11 M.Abs or not. Leu 11- T cells (referred to as Type 1) were inhibited by M.Abs to T3, T8, and a common HLA, ABC antigen. Conversely Leu 11+ T cells (referred to as Type 2) were inhibited by M.Ab to Leu 11 but not by M.Ab to T3, T8 and the HLA, ABC antigen. Subtypes among Type 1 cells were recognized which depended on their specificity. The most restricted were CTL [Type 1(a)] clones generated only in MLTC which recognized the autologous melanoma cell plus 1 of 11 other melanoma target cells. Type 1(b) CTL clones recognized a larger proportion (approximately 50%) of the melanoma cells. A third category [Type 1(c)] recognized antigens on melanoma cells shared with that on the EBV-transformed B cells used as stimulators in the MLC. Type 2 CTL clones had broad specificity to melanoma and nonmelanoma cells, characteristic of that described for lymphokine activated killer (LAK) cells. The latter were MHC unrestricted but further studies are required to clarify whether the Type 1 CTL clones are MHC restricted or not. The CTL activity of all clones was inhibited by M.Ab to the sheep red blood cell receptor and to the T10 antigens. It is suggested that recognition of these different types of CTL clones may assist future studies on the immune response against melanoma and the nature of antigens recognized by CTL.

Antibodies, Monoclonal↗
PubMed1986

Comparative study on the effects of recombinant alpha-2 interferon on immune function in patients with disseminated melanoma.

Fifteen patients with disseminated melanoma were treated by intravenous administration of recombinant alpha-2 interferon (rIFN-alpha 2) on 5 consecutive days every 2 weeks. Immunological studies on approximately 50% of the patients revealed no significant changes in lymphocyte numbers or T-cell subsets. Natural killer (NK) activity against the K562 target cell and a melanoma cell was increased in the first treatment cycle, but in subsequent treatment cycles it tended to decrease against the melanoma cell and to show either no change or moderate increases against the K562 target cell. Interleukin-2 (IL-2) production from mitogen-stimulated lymphocytes was decreased in most patients in each treatment cycle. This also applied to immunoglobulin production in vitro from pokeweed mitogen (PWM)-stimulated B and T cells. The latter was not due to the induction of radiation-sensitive suppressor T cells and may reflect effects on B cells or helper T cells. The repeated inhibition of IL-2 production with each cycle of treatment and the decrease in NK activity against the melanoma target cells after the first treatment cycle contrasted with the return to at or above pretreatment values of these tests when rIFN-alpha A was given intramuscularly on an alternate-day basis. It is suggested that these effects may be due to the relatively greater increase in endogenous cortisol production at the beginning of each treatment cycle in patients given rIFN-alpha 2 intravenously compared to that observed in patients treated with rIFN-alpha A on alternate days intramuscularly. Immunosuppression resulting from the increase in cortisol production may be one of the factors accounting for the low tumor response rate of patients in this study and may emphasize the possible importance of the schedule of rIFN-alpha administration for obtaining optimal antitumor responses.

Adult↗
PubMed1985

Effects of recombinant leukocyte interferon (rIFN-alpha A) on tumour growth and immune responses in patients with metastatic melanoma.

Studies were initiated to assess the response of patients with disseminated melanoma to recombinant alpha interferon (rIFN-alpha A) and to monitor effects of rIFN-alpha A on several tests of immune function. Twenty patients were treated with rIFN-alpha A given by i.m. injection in escalating doses from 15 to 50 X 10(6) um-2. The responses of two patients were considered unevaluable. Of the remainder there was complete remission of tumour in two and stable disease in two. Subsequent progression of tumour in one of the latter patients coincided with development of antibodies to IFN. Side effects (usually fatigue) were dose rate limiting in 11 patients. Laboratory tests on samples taken 6 hours after rIFN-alpha A indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity particularly against K562 target cells. Longer term changes measured in samples taken 2 days after the previous rIFN-alpha A injections consisted of neutropenia and an increase in the T4/T8 ratio due mainly to a relative increase in OKT4 positive T cells compared to OKT8 positive T cells. NK activity against the K562 target cell increased in most patients during the first week of treatment and then returned to below or near pretreatment levels thereafter against the K562 target cell. This contrasted with NK activity against the melanoma target cell which showed a more gradual increase over the duration of the treatment in 6 patients. The latter correlated with an increase in mitogen stimulated IL 2 production from their blood lymphocytes and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. These results confirm the activity of rIFN-alpha A against melanoma in certain patients. They suggest that further studies are needed to select patients who may respond to rIFN-alpha A and to optimize treatment regimens. Tests of IL 2 production and LAK activity may assisted in achieving these objectives.

Adult↗